Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis.

Abstract

Cholesteryl ester storage disease (CESD) is characterized by the deficient activity of lysosomal cholesteryl ester (CE) hydrolase, accumulation of LDL-derived CE in lysosomes, and hyperlipidemia. We studied the kinetics of VLDL and LDL apolipoprotein B (apoB), using 125I-VLDL and "1I-LDL, in a 9-yr-old female with CESD and elevated total cholesterol (TC) (271.0±4.4 mg/dl), triglyceride (TG) (150.0±7.8 mg/dl), and LDL cholesterol (184.7±3.4 mg/dl). These studies demonstrated a markedly elevated production rate (PR) of apoB, primarily in LDL, with normal fractional catabolism of apoB in VLDL and LDL. Urine mevalonate levels were elevated, indicative of increased synthesis of endogenous cholesterol. Treatment with lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, resulted in significant reductions in TC (196.8±7.9 mg/dl), TG (100.8±20.6 mg/dl), and LDL cholesterol (102.0±10.9 mg/dl). Therapy reduced VLDL apoB PR (5.2 vs. 12.2 mg/kg per d pretreatment) and LDL apoB PR (12.7 vs. 24.2 mg/kg per d pretreatment). Urine mevalonate levels also decreased during therapy. These results indicate that, in CESD, the inability to release free cholesterol from lysosomal CE resulted in elevated synthesis of endogenous cholesterol and increased production of apoB-containing lipoproteins. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apoB-containing lipoproteins.

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

“…Following the receptor-mediated cell endocytosis of LDL, the hydrolysis of LDL-derived cholesteryl esters is catalyzed in the lysosome by LAL. Therefore, a defi ciency of this enzyme would result in the lysosmal accumulation of esterifi ed cholesterol and in a relative depletion of free cholesterol, which may likely cause the activation of endogenous cholesterol biosynthesis by the upregulation of HMG-CoA reductase, resulting in the characteristic hypercholesterolemia observed in these patients and contributing to the formation of oxysterols ( 20,21 ). free cholesterol from the lysosomal compartment ( 18 ).…”

ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes

“…In support of this is the decrease in VLDL production in whole animals and in man (27)(28)(29)(30)(31), as well as in cultured primary hepatocytes (32), following treatment with HMG-CoA reductase inhibitors. These results suggest that the availability and/or distribution of hepatocyte cholesterol plays an important role in the assembly of nascent apoB particles within the endoplasmic reticulum and that perturbations of this tightly regulated system have major effects on VLDL secretion.…”

Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice

“…For CESD, therapeutic efforts have focused on diminishing the accumulation of CEs within the liver and spleen using HMG-CoA-reductase inhibitors. Some effects have been observed on lipoprotein metabolism, but no consistent phenotypic or outcome effects are apparent with these agents (8). A combination therapy of lovastatin and ezetimibe, an inhibitor of the Niemann-Pick type C1-like gene product that regulates sterol absorption in the small intestine (9)(10)(11), led to enhanced effects on lowering plasma LDL-cholesterol in one CESD patient (12).…”